Towards understanding how bisphosphonate-dependent alterations to nutrient canal integrity can contribute to risk for atypical femoral fractures: Biomechanical considerations and potential relationship to a real-world analogy.

Bisphosphonates are a class of drugs which have shown good efficacy in the treatment of post-menopausal osteoporosis, as well as a good safety profile. However, side-effects such as risk for atypical femoral fractures (AFF) have appeared, leading to a decline in use of the drugs by many patients who would benefit from the treatment. While patient characteristics have contributed to improved understanding of risk factors, the mechanisms involved that explain AFF risk have not appeared. Recently, the possibility that the mechanism(s) involved drug-induced modification of cells of the nutrient canals of the femur and subsequent compromise in the bone matrix has been published. The present Hypothesis article builds on the concept presented earlier and expands into biomechanical considerations. An analogy of the mechanisms involved to a real-life scenario is also presented. While this analogy has limitations, consideration of the biomechanical implications of progressive alterations to defects presented by compromised nutrient canal-bone matrix also presents potential relationships with AFF risk.

Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature.

BACKGROUND: Weill-Marchesani syndrome (WMS) belongs to the group of acromelic dysplasias, defined by short stature, brachydactyly and joint limitations. WMS is characterised by specific ophthalmological abnormalities, although cardiovascular defects have also been reported. Monoallelic variations in FBN1 are associated with a dominant form of WMS, while biallelic variations in ADAMTS10, ADAMTS17 and LTBP2 are responsible for a recessive form of WMS. OBJECTIVE: Natural history description of WMS and genotype-phenotype correlation establishment. MATERIALS AND METHODS: Retrospective multicentre study and literature review. INCLUSION CRITERIA: clinical diagnosis of WMS with identified pathogenic variants. RESULTS: 61 patients were included: 18 individuals from our cohort and 43 patients from literature. 21 had variants in ADAMTS17, 19 in FBN1, 19 in ADAMTS10 and 2 in LTBP2. All individuals presented with eye anomalies, mainly spherophakia (42/61) and ectopia lentis (39/61). Short stature was present in 73% (from -2.2 to -5.5 SD), 10/61 individuals had valvulopathy. Regarding FBN1 variants, patients with a variant located in transforming growth factor (TGF)-ß-binding protein-like domain 5 (TB5) domain were significantly smaller than patients with FBN1 variant outside TB5 domain (p=0.0040). CONCLUSION: Apart from the ophthalmological findings, which are mandatory for the diagnosis, the phenotype of WMS seems to be more variable than initially described, partially explained by genotype-phenotype correlation.

Are secondary effects of bisphosphonates on the vascular system of bone contributing to increased risk for atypical femoral fractures in osteoporosis?

Osteoporosis (OP) is a bone disease which affects a number of post-menopausal females and puts many at risk for fractures. A large number of patients are taking bisphosphonates (BPs) to treat their OP and a rare complication is the development of atypical femoral fractures (AFF). No real explanations for the mechanisms underlying the basis for development of where AFF develop while on BPs has emerged. The present hypothesis will discuss the possibility that part of the risk for an AFF is a secondary effect of BPs on a subset of vascular cells in a genetically at-risk population, leading to localized deregulation of the endothelial cell (EC)-bone cell-matrix units in nutrient channels/canals of the femur and increased risk for AFF. This concept of targeting ECs is consistent with location of AFF in the femur, the bilateral risk for occurrence of AFF, and the requirement for long term exposure to the drugs.

Bone metabolism in diabetes: a clinician's guide to understanding the bone-glucose interplay.

Skeletal fragility is an increasingly recognised, but poorly understood, complication of both type 1 and type 2 diabetes. Fracture risk varies according to skeletal site and diabetes-related characteristics. Post-fracture outcomes, including mortality risk, are worse in those with diabetes, placing these people at significant risk. Each fracture therefore represents a sentinel event that warrants targeted management. However, diabetes is a very heterogeneous condition with complex interactions between multiple co-existing, and highly correlated, factors that preclude a clear assessment of the independent clinical markers and pathophysiological drivers for diabetic osteopathy. Additionally, fracture risk calculators and routinely used clinical bone measurements generally underestimate fracture risk in people with diabetes. In the absence of dedicated prospective studies including detailed bone and metabolic characteristics, optimal management centres around selecting treatments that minimise skeletal and metabolic harm. This review summarises the clinical landscape of diabetic osteopathy and outlines the interplay between metabolic and skeletal health. The underlying pathophysiology of skeletal fragility in diabetes and a rationale for considering a diabetes-based paradigm in assessing and managing diabetic bone disease will be discussed.

Exome Sequencing for the Diagnostics of Osteogenesis Imperfecta in Six Russian Patients.

Osteogenesis imperfecta (OI) is a group of inherited disorders of connective tissue that cause significant deformities and fragility in bones. Most cases of OI are associated with pathogenic variants in collagen type I genes and are characterized by pronounced polymorphisms in clinical manifestations and the absence of clear phenotype-genotype correlation. The objective of this study was to conduct a comprehensive molecular-genetic and clinical analysis to verify the diagnosis of OI in six Russian patients with genetic variants in the COL1A1 and COL1A2 genes. Clinical and laboratory data were obtained from six OI patients who were observed at the Medical Genetics Center in Saint Petersburg from 2016 to 2023. Next-generation sequencing on MGISEQ G400 (MGI, China) was used for DNA analysis. The GATK bioinformatic software (version 4.5.0.0) was used for variant calling and hard filtering. Genetic variants were verified by the direct automatic sequencing of PCR products using the ABI 3500X sequencer. We identified six genetic variants, as follows pathogenic c.3505G>A (p. Gly1169Ser), c.769G>A (p.Gly257Arg), VUS c.4123G>A (p.Ala1375Thr), and c.4114A>T (p.Asn1372Tyr) in COL1A1; and likely pathogenic c.2035G>A (p.Gly679Ser) and c.739-2A>T in COL1A2. In addition, clinical cases are presented due to the presence of the c.4114A>T variant in the COL1A2 gene. Molecular genetics is essential for determining different OI types due to the high similarity across various types of the disease and the failure of unambiguous diagnosis based on clinical manifestations alone. Considering the variable approaches to OI classification, an integrated strategy is required for optimal patient management.

Fibroblast growth factor 23 and its role in bone diseases.

Fibroblast growth factor 23 (FGF23) has been casually linked to numerous hypophosphatemic bone diseases, however connection with bone loss or fragility fractures is still a matter of debate. The purpose of this review is to explore and summarise the known actions of FGF23 in various pathological bone conditions. Besides implication in bone mineralisation, elevated FGF23 showed a pathological effecton bone remodelling, primarily by inhibiting osteoblast function. Unlike the weak association with bone mineral density, high values of FGF23 have been connected with fragility fracture prevalence. This review shows that its effects on bone are concomitantly present on multiple levels, affecting both qualitative and quantitative part of bone strength, eventually leading to impaired bone strength and increased tendency of fractures. Recognising FGF23 as a risk factor for the development of bone diseases and correcting its levels could lead to the reduction of morbidity and mortality in specific groups of patients.

Opioid use and adverse health effects in breast cancer survivors.

BACKGROUND: Little information exists on adverse effects related to opioid use in breast cancer survivors following active cancer treatment, and no studies included an age-matched comparison group. Thus, we examined opioid use and risk of falls, fractures, lung problems, and cardiovascular events in breast cancer survivors in the years following active cancer treatment along with a comparison group. METHODS: We conducted a longitudinal cohort study 33 989 breast cancer survivors and 157 609 age-matched women without cancer. Rates of adverse events, and multivariable hazards ratios for association between opioid use and the adverse health effects were calculated. RESULTS: Women with breast cancer had greater opioid use (60% vs 48%); longer median opioid duration (18 vs 16 days); and were prescribed stronger opioids than the matched cohort over 5.6 median years of follow-up. In multivariable models, the risk of falls was 12% higher (HR, 95% CI, 1.12 [1.07-1.17]), and fracture risk was 56% (HR = 1.56 [1.48-1.65]) greater in women with breast cancer who used opioids vs the matched cohort unexposed to opioids. In an analysis restricted to women with breast cancer, opioid use was strongly associated with the risk of falls (HR = 1.74 [1.63-1.85]); fractures (HR = 2.10 [1.95-2.27]); lung problems (HR = 1.53 [1.43-1.64]); and cardiovascular events (HR = 1.70 [1.39-2.08]) than opioid non-use. CONCLUSIONS: After active cancer treatment, opioid use and high dosage use were common in breast cancer survivors, and were associated with increased risk for falls, lung problems, fractures, and cardiovascular events. Findings underscore the need for careful monitoring of opioid use in these survivors and the exploration of alternative pain management strategies.

Pediatric wrist fractures: variations in management across countries. An evidence-based summary of evidence.

INTRODUCTION: Fractures of the distal radius are common in pediatric population, with considerable variation in the management of pediatric wrist fractures across different countries. It is crucial to consider the different approaches to conservative management and surgical intervention. The decision on the appropriate treatment method often depends on the type and severity of the fracture, as well as the available healthcare resources and expertise in each country. This article tries to identify these variations, so the various healthcare systems can work toward implementing best practices in the management of pediatric wrist fractures on a global scale. SOURCE OF DATA: Published peer-reviewed articles identified in electronic databases, including PubMed Scopus and Google Scholar. AREAS OF AGREEMENT: The management of pediatric wrist fractures can differ significantly among countries given the high variability in healthcare resources and cultural practices. AREAS OF CONTROVERSY: The management of pediatric wrist fractures can be challenging in certain countries, especially in developing regions with limited resources. GROWING POINTS: Challenges such as long therapeutic delays, lack of appropriate anesthesia, and the absence of fluoroscopy can complicate the treatment process. Randomized controlled clinical trials (RCTs) are vital in providing high-quality evidence to guide clinical decision-making, especially in the field of pediatric wrist fractures. AREAS TIMELY FOR DEVELOPING RESEARCH: Efforts to support and prioritize the conduct and dissemination of RCTs in pediatric wrist fracture management can ultimately lead to more consistent, effective, and evidence-based care for children with wrist fractures worldwide.

Microbial life in preferential flow paths in subsurface clayey till revealed by metataxonomy and metagenomics.

BACKGROUND: Subsurface microorganisms contribute to important ecosystem services, yet little is known about how the composition of these communities is affected by small scale heterogeneity such as in preferential flow paths including biopores and fractures. This study aimed to provide a more complete characterization of microbial communities from preferential flow paths and matrix sediments of a clayey till to a depth of 400 cm by using 16S rRNA gene and fungal ITS2 amplicon sequencing of environmental DNA. Moreover, shotgun metagenomics was applied to samples from fractures located 150 cm below ground surface (bgs) to investigate the bacterial genomic adaptations resulting from fluctuating exposure to nutrients, oxygen and water. RESULTS: The microbial communities changed significantly with depth. In addition, the bacterial/archaeal communities in preferential flow paths were significantly different from those in the adjacent matrix sediments, which was not the case for fungal communities. Preferential flow paths contained higher abundances of 16S rRNA and ITS gene copies than the corresponding matrix sediments and more aerobic bacterial taxa than adjacent matrix sediments at 75 and 150 cm bgs. These findings were linked to higher organic carbon and the connectivity of the flow paths to the topsoil as demonstrated by previous dye tracer experiments. Moreover, bacteria, which were differentially more abundant in the fractures than in the matrix sediment at 150 cm bgs, had higher abundances of carbohydrate active enzymes, and a greater potential for mixotrophic growth. CONCLUSIONS: Our results demonstrate that the preferential flow paths in the subsurface are unique niches that are closely connected to water flow and the fluctuating ground water table. Although no difference in fungal communities were observed between these two niches, hydraulically active flow paths contained a significantly higher abundance in fungal, archaeal and bacterial taxa. Metagenomic analysis suggests that bacteria in tectonic fractures have the genetic potential to respond to fluctuating oxygen levels and can degrade organic carbon, which should result in their increased participation in subsurface carbon cycling. This increased microbial abundance and activity needs to be considered in future research and modelling efforts of the soil subsurface.

Is Early Menopause a Different Entity From Premature Ovarian Insufficiency?

Premature ovarian insufficiency (POI, defined as age at menopause < 40 years) affects 1%-3% of postmenopausal women. It is positively associated with an increased risk of diabetes mellitus, arterial hypertension, cardiovascular disease, osteoporosis, fractures, cognitive impairment, and depression. Early menopause (EM, defined as age at menopause < 45 years) is also associated with these adverse health consequences, in most cases to the same degree as in POI. Therefore, a unifying term for EM and POI, such as 'premature menopause', may be proposed, using the age threshold of < 45 years. This could provide broader coverage of these women, substantiating the need for prompt administration of menopausal hormone therapy (in this case, 'hormone replacement therapy'). However, the benefits of this approach, which precludes a higher oestrogen dose up to the normal age of menopause, need to be proven in well-designed randomized controlled trials.

Bone health in women with premature ovarian insufficiency/early menopause: a 23-year longitudinal analysis.

STUDY QUESTION: What is the frequency of, and predictors for, osteoporosis, fractures, and osteoporosis management (investigation, treatment) in women with premature ovarian insufficiency (POI; menopause <40 years) and early menopause (EM; menopause 40-44years)? SUMMARY ANSWER: Over the 23-year follow-up duration, at a mean age of 68 years, women with POI/EM had higher osteoporosis/fracture risk and prevalence, higher osteoporosis screening and anti-osteoporosis medication use compared to women with usual age menopause; increasing age was predictive of increased risk of osteoporosis/fracture and menopause hormone therapy (MHT) prior to or at study entry (aged 45-50 years) was protective. WHAT IS KNOWN ALREADY: Women with POI/EM have increased risk of osteoporosis and fractures with limited data regarding risk factors for reduced bone density and fractures. Clinical guidelines recommend screening with dual X-ray absorptiometry (DXA) and treatment with MHT for most women with POI/EM to reduce osteoporosis and fracture risk; however, studies indicate gaps in osteoporosis knowledge, guideline uptake, and management adherence by clinicians and women. STUDY DESIGN, SIZE, DURATION: The Australian Longitudinal Study on Women's Health is a prospective longitudinal study of Australian women. This study uses the cohort of women born between 1946 and 1951, surveyed nine times between 1996 and 2019. Data from the Australian administrative health records, including hospital admissions data (fractures, osteoporosis), Medicare Benefits Schedule (DXA), and the Pharmaceutical Benefits Scheme (PBS; MHT, anti-osteoporosis medication, available only from 2002) were linked to survey data. PARTICIPANTS/MATERIALS, SETTING, METHODS: Survey respondents with self-reported age of menopause were included. POI/EM was defined as menopause <45 years. T-test or chi-square were used for comparisons at baseline (P < 0.05 indicates significance). Generalized estimating equations for panel data explored predictors for the longitudinal outcomes of osteoporosis, fractures, DXA rates, MHT use, and anti-osteoporosis medication (in women with osteoporosis/fracture, from Survey 4 onwards only). Univariable regression was performed, and variables retained where P < 0.2, to form the multivariable model, and bootstrapping with 100 repetitions at 95% sampling of the original dataset to ensure robustness of results. MAIN RESULTS AND THE ROLE OF CHANCE: Eight thousand six hundred and three women were included: 610 (7.1%) with POI/EM. Mean (SD) baseline age was 47.6 (1.45) years in the entire cohort and mean (SD) age of menopause was 38.2 (7.95) and 51.3 (3.04) years in women with POI/EM and usual age menopause, respectively (P < 0.001). Over the 23 years, of women with POI/EM, 303 (49.7%) had osteoporosis/fractures, 421 (69.0%) had DXA screening, 474 ever used MHT (77.7%), and 116 (39.1%) of those with osteoporosis/fractures used anti-osteoporosis medication. Of women with usual age menopause, 2929 (36.6%) had osteoporosis/fractures, 4920 (61.6%) had DXA screening, 4014 (50.2%) used MHT, and 964 (33.0%) of those with osteoporosis/fractures used anti-osteoporosis medication. Compared to women with menopause at age ≥45 years and after adjusting for other risk factors, women with POI/EM had increased risk of osteoporosis (odds ratio [OR] 1.37; 95% CI 1.07-1.77), fractures (OR 1.45; 1.15-1.81), DXA testing (OR 1.64; 1.42-1.90), MHT use (OR 6.87; 5.68-8.30), and anti-osteoporosis medication use (OR 1.50; 1.14-1.98). In women with POI/EM women, increasing age was associated with greater risk of osteoporosis/fracture (OR 1.09; 1.08-1.11), and MHT prior to or at study entry (aged 45-50 years), was protective (OR 0.65, 0.45-0.96). In women with POI/EM, age (OR 1.11; 1.10-1.12), fractures (OR 1.80, 1.38-2.34), current smoking (OR 0.60; 0.43-0.86), and inner (OR 0.68; 0.53-0.88) or outer regional (OR 0.63; 0.46-0.87) residential location were associated with DXA screening. In women with POI/EM, increasing age (OR 1.02; 1.01-1.02), and currently consuming alcohol (OR 1.17; 1.06-1.28), was associated with having ever used MHT. In the 299 women with POI/EM and osteoporosis/fractures, only 39.1% ever received treatment with an anti-osteoporosis medication. Increasing age (OR 1.07; 1.04-1.09) and lower BMI (OR 0.95; 0.92-0.98) were associated with greater likelihood of treatment with anti-osteoporosis medication. LIMITATIONS, REASONS FOR CAUTION: Survey data including age of menopause were self-reported by participants; fracture questions were not included in the 2001 survey, and location or level of trauma of self-reported fractures was not asked. Additional risk/protective factors such as vitamin D status, calcium intake, and exercise were not able to be included. Due to sample size, POI and EM were combined for all analyses, and we were unable to differentiate between causes of POI/EM. PBS data were only available from 2004, and hospital admissions data were state-based, with all of Australia were only available from 2007. WIDER IMPLICATIONS OF THE FINDINGS: This study supports previous literature indicating increased risk of osteoporosis and fractures in women with POI, and adds evidence for women with POI/EM, where there was a relative paucity of data. This is the first study to analyse a variety of clinical and demographic risk factors for osteoporosis and fractures in women with POI/EM, as well as analysing investigation and treatment rates. In these women, using MHT prior to or at study entry, aged 45-50 years, was protective for osteoporosis/fractures; however, having ever used MHT was not, highlighting the importance of early treatment with MHT in these women to preserve bone strength. Although women with POI/EM and osteoporosis or fractures were more likely to use anti-osteoporosis medications than those with usual age menopause, overall treatment rates are low at <40%, demonstrating a significant treatment gap that should be addressed to reduce future fracture risk. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Australian NHMRC Centre of Research Excellence Women's Health in Reproductive Life (CRE-WHIRL, project number APP1171592). A.R.J. is the recipient of a National Health and Medical Research Council post-graduate research scholarship (grant number 1169192). P.R.E. is supported by a National Health and Medical Research Council grant 1197958. P.R.E. reports grants paid to their institution from Amgen, Sanofi, and Alexion, honoraria from Amgen paid to their institution, and honoraria from Alexion and Kyowa-Kirin. TRIAL REGISTRATION NUMBER: N/A.

Epidemiology of forearm fractures in women and men in Norway 2008-2019.

The purpose of this paper is to describe rates of forearm fractures in adults in Norway 2008-2019. Incidence rate of distal forearm fractures declined over time in both sexes. Forearm fracture constitute a significant health burden and prevention strategies are needed. PURPOSE: To assess age- and sex-specific incidence rates, and time trends for forearm fractures in Norway, and compare these with incidence rates in other Nordic countries. METHODS: Data on all patients aged 20-107 years with forearm fractures treated in Norwegian hospitals from 2008 to 2019 was retrieved from the Norwegian Patient Registry. Fractures were identified based on International Classification of Disease 10th revision code S52. Age- and sex-specific incidence rates and changes in incidence rates were calculated. RESULTS: We identified 181,784 forearm fractures in 45,628,418 person-years. Mean annual forearm fracture incidence rates per 100,000 person-years were 398 (95% CI 390-407) for all, 565 (95% CI 550-580) for women, and 231 (95% CI 228-234) for men above 20 years. Mean annual number of forearm fractures was 15,148 (95% CI 14,575-15,722). From 2008 to 2019, age-adjusted total incidence rates of forearm fractures S52 diagnoses declined by 3.5% (incidence rate ratio (IRR) of 0.997 (95% CI 0.994-0.999)) in men. The corresponding decline in women was not significant (IRR: 0.999 (95% CI 0.997-1.002)). In the same period, the age-adjusted incidence rates of distal forearm fractures declined by 7.0% in men (IRR = 0.930; 95% CI 0.886-0.965) and 4.7% in women (IRR = 0.953; 95% CI 0.919-0.976). The incidence rates of distal forearm fractures were similar to rates in Sweden and Finland. CONCLUSION: Age-adjusted incidence rates of distal forearm fractures in both sexes declined over time.

Family/caregiver influence on osteoporosis management for older people: an integrative review.

An integrative literature review was conducted to understand family/caregiver influence on osteoporosis management for older people. Findings include caregivers' overprotection, caregivers' risks for fragility fractures due to caregiving role, poor bone health in caregivers, and caregivers' burden and facilitators. Caregivers should be included in bone health and discharge planning. Literature on family/caregiver influence on osteoporosis management for older people is sparse. Older people are prone to osteoporosis and fragility fractures due to their age, often triggering the need for a caregiver after experiencing a fragility fracture. These fractures pose significant costs to the patient and health systems and are projected to increase with the aging population. This study applied an integrative literature review methodology to key literature findings on family/caregiver influence on osteoporosis management for older people. Key findings include caregivers' tendency to overprotect persons who experience hip fracture by limiting mobilization, thus impeding recovery, caregivers' risks for their own fragility fractures due to the demands of their caregiving role, risks of poor bone health in caregivers, and caregivers' experience of significant burden for which facilitators have been identified. Family caregivers of older people with osteoporosis have unique needs and require support and resources, especially after their loved one experiences a hip fracture. Informal caregivers must be considered in bone health education and discharge planning. They should be considered in the creation of osteoporosis guidelines and within the work of fracture liaison services. More research is needed to increase understanding about family caregiver influence on osteoporosis management.

The effect of romosozumab on bone mineral density depending on prior treatment: a prospective, multicentre cohort study in Switzerland.

This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip. INTRODUCTION: In Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies. METHODS: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients. RESULTS: Ninety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level. CONCLUSION: Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip.

Low-dose glucocorticoid increase the risk of fracture in postmenopausal women with low bone mass: a retrospective cohort study.

Long-term glucocorticoids (GCs) treatment is associated with osteoporosis and fractures. We investigated whether low-dose GC treatment also increased the risk of osteoporotic fractures, and the results showed that even low-dose GC treatment increased the risk of osteoporotic fractures, especially spine fractures. PURPOSE: The effect of low-dose glucocorticoid (GC) therapy on the fracture risk in postmenopausal women with low bone mass was investigated. METHODS: 119,790 66-year-old postmenopausal women with low bone mass based on bone mineral density (BMD) results were included. GC group consisted of patients who had been prescribed oral GCs within 6 months of BMD testing. In GC group, GCs dosage was calculated by a defined daily dose (DDD), and divided into five groups according to GC usage (Group 1[G1]; < 11.25 DDDs, G2; ≥ 11.25, < 22.5 DDDs, G3; ≥ 22.5, < 45 DDDs, G4; ≥ 45, < 90 DDDs, G5; ≥ 90 DDDs). The risk of major osteoporotic fractures (MOF) and non-MOF was analyzed and compared with that of the control group during the 1-year follow-up. RESULTS: The risk of total fracture was higher in G3-G5 than in the control group (G3, hazard ratio (HR) 1.25, 95% confidence interval [CI] 1.07-1.46; G4, 1.37 [1.13-1.66]; G5 1.45 [1.08-1.94]). The risk of MOF was higher in all groups except G2 than in the control group (G1, 1.23 [1.05-1.45]; G3, 1.37 [1.11-1.68]; G4, 1.41 [1.09-1.83]; G5, 1.66 [1.14-2.42]). The risk of spine fracture was significantly higher in all GC groups except G2 than in the control group. The risk of non-MOF was higher only in G4 than in the control group (G4, 1.48 [1.13-1.94]). CONCLUSION: Low-dose GC therapy can increase the risk of osteoporotic fractures, particularly spine fractures, in postmenopausal women with low bone mass.

Chemokine CXCL9, a marker of inflammaging, is associated with changes of muscle strength and mortality in older men.

Our study examined associations of the CXC motif chemokine ligand 9 (CXCL9), a pro-inflammatory protein implicated in age-related inflammation, with musculoskeletal function in elderly men. We found in certain outcomes both cross-sectional and longitudinal significant associations of CXCL9 with poorer musculoskeletal function and increased mortality in older men. This requires further investigation. PURPOSE: We aim to determine the relationship of (CXCL9), a pro-inflammatory protein implicated in age-related inflammation, with both cross-sectional and longitudinal musculoskeletal outcomes and mortality in older men. METHODS: A random sample from the Osteoporotic Fractures in Men (MrOS) Study cohort (N = 300) was chosen for study subjects that had attended the third and fourth clinic visits, and data was available for major musculoskeletal outcomes (6 m walking speed, chair stands), hip bone mineral density (BMD), major osteoporotic fracture, mortality, and serum inflammatory markers. Serum levels of CXCL9 were measured by ELISA, and the associations with musculoskeletal outcomes were assessed by linear regression and fractures and mortality with Cox proportional hazards models. RESULTS: The mean CXCL9 level of study participants (79.1 ± 5.3 years) was 196.9 ± 135.2 pg/ml. There were significant differences for 6 m walking speed, chair stands, physical activity scores, and history of falls in the past year across the quartiles of CXCL9. However, higher CXCL9 was only significantly associated with changes in chair stands (ß = - 1.098, p < 0.001) even after adjustment for multiple covariates. No significant associations were observed between CXCL9 and major osteoporotic fracture or hip BMD changes. The risk of mortality increased with increasing CXCL9 (hazard ratio quartile (Q)4 vs Q1 1.98, 95% confidence interval 1.25-3.14; p for trend < 0.001). CONCLUSIONS: Greater serum levels of CXCL9 were significantly associated with a decline in chair stands and increased mortality. Additional studies with a larger sample size are needed to confirm our findings.

The significance of recent fracture location for imminent risk of hip and vertebral fractures-a nationwide cohort study on older adults in Sweden.

The role of recent fracture site in predicting the most detrimental subsequent fractures, hip and vertebral, is unclear. This study found that most recent fracture sites were associated with an increased risk of both hip and vertebral fracture, a finding that may impact the design of secondary prevention programs. BACKGROUND: Hip and vertebral fractures are the most serious in terms of associated morbidity, mortality, and societal costs. There is limited evidence as to which fracture types are associated with the highest risk for subsequent hip and vertebral fractures. This study aims to explore the dependency of imminent hip and vertebral fracture risk on the site of the recent index fracture. METHODS: Conducted as a nationwide retrospective cohort study, we utilized Swedish national registers to assess the risk of hip and vertebral fractures based on the site of the recent (≤ 2 years) index fracture and an old (> 2 years) prevalent fracture. This risk was compared to that observed in individuals without any prevalent fractures. This study encompassed all Swedes aged 50 years and older between 2007 and 2010. Patients with a recent fracture were categorized into specific groups based on the type of their previous fracture and were followed until December 2017, with censoring for death and migration. The study assessed the risk of hip and vertebral fractures during the follow-up period. RESULTS: The study included a total of 3,423,320 individuals, comprising 145,780 with a recent fracture, 293,051 with an old fracture, and 2,984,489 without a previous fracture. The median follow-up times for the three groups were 7.6 years (IQR 4.0-9.1), 7.9 years (5.8-9.2), and 8.5 years (7.4-9.7), respectively. Patients with a recent fracture at almost all sites exhibited a significantly increased risk of hip fracture and an elevated risk of vertebral fracture compared to controls. Patients with recent fractures had an increased risk of subsequent hip and vertebral fractures, regardless of the index fracture site. These results strengthen the notion that all patients with a recent fracture, regardless of fracture site, should be included in secondary prevention programs, to improve the prevention of the clinically most serious fractures.

Vertebral fracture severity assessment on anteroposterior radiographs with a new semi-quantitative technique.

We developed a new tool to assess the severity of osteoporotic vertebral fracture using radiographs of the spine. Our technique can be used in patient care by helping to stratify patients with osteoporotic vertebral fractures into appropriate treatment pathways. It can also be used for research purposes. PURPOSE: The aim of our study was to propose a semi-quantitative (SQ) grading scheme for osteoporotic vertebral fracture (OVF) on anteroposterior (AP) radiographs. METHODS: On AP radiographs, the vertebrae are divided into right and left halves, which are graded (A) vertical rectangle, (B) square, (C) traverse rectangle, and (D) trapezoid; whole vertebrae are graded (E) transverse band or (F) bow-tie. Type A and B were compared with normal and Genant SQ grade 1 OVF, Type C and D with grade 2 OVF, and Type E and F with grade 3 OVF. Spine AP radiographs and lateral radiographs of 50 females were assessed by AP radiographs SQ grading. After training, an experienced board-certified radiologist and a radiology trainee assessed the 50 AP radiographs. RESULTS: The height-to-width ratio of the half vertebrae varied 1.32-1.48. On lateral radiographs, 84 vertebrae of the 50 patients had OVFs (38 grade 1, 24 grade 2, and 22 grade 3). On AP radiographs, the radiologist correctly assigned 84.2%, 91.7%, and 77.2% and the trainee correctly assigned 68.4%, 79.2%, and 81.8% of grade 1, 2, and 3 OVFs, respectively. Compared with lateral radiographs, the radiologist had a weighted Kappa of 0.944 including normal vertebrae and 0.883 not including normal vertebrae, while the corresponding Kappa values for the trainee were 0.891 and 0.830, respectively. CONCLUSION: We propose a new semi-quantitative grading system for vertebral fracture severity assessment on AP spine radiographs.

Should major trauma fractures be part of a fracture liaison service's remit: a cost-benefit estimate.

The refracture rate after major trauma is approximately half (57%) the refracture rate after a minimal trauma injury. Extending Fracture Liaison Service activity to include major trauma patients creates significant additional direct cost, but remains essentially cost neutral if notional savings through refracture risk reduction are taken into account. PURPOSE: To compare the 3-year refracture rate following minimal trauma (MT) and non-minimal trauma (non-MT) injuries and evaluate the cost of extending fracture liaison service (FLS) operations to non-MT presentations. METHODS: Patients aged 50, or above presenting to the John Hunter Hospital with a fracture in calendar year 2018 were identified through the Integrated Patient Management System (IPMS) of the Hunter New England Health Service's (HNEHS), and re-presentation to any HNEHS facility over the following 3 years monitored. The refracture rate of MT and non-MT presentations was compared and analysed using Cox proportional hazards regression models. The cost of including non-MT patients was estimated through the use of a previously conducted micro-costing analysis. The operational fidelity of the FLS to the previous estimate was confirmed by comparing the 3-year refracture rate of MT presentations in the two studies. RESULTS: The 3-year refracture rate following a MT injury was 8% and after non-MT injury 4.5%. Extension of FLS activities to include non-MT patients in 2022 would have cost an additional $198,326 AUD with a notional loss/saving of $ - 26,625/ + 26,913 AUD through refracture risk reduction. No clinically available characteristic at presentation predictive of increased refracture risk was identified. CONCLUSION: The 3-year refracture after a non-MT injury is about half (57%) that of the refracture rate after a MT injury. Extending FLS activity to non-MT patients incurs a significant additional direct cost but remains cost neutral if notional savings gained through reduction in refracture risk are taken into account.

Osteoporotic vertebral fractures localized in the lumbar area significantly impact sagittal alignment.

Lumbar fractures and/or multiple fractures at the lumbar or thoracolumbar regions are risk factors for sagittal malalignment in patients older than 70 years old. Although patients with OVF show a huge capacity to compensate after the fractures, lumbar and TL lumbar fractures require closer monitoring. PURPOSE: To assess the impact of osteoporotic vertebral fractures on the sagittal alignment of the elderly and identify risk factors for sagittal malalignment. METHODS: We performed a retrospective study on a cohort of 249 patients older than 70 years old and diagnosed with osteoporosis who suffered chronic vertebral fractures. Demographic and radiological data were collected. Full-spine lateral X-rays were obtained to analyze the sagittal plane. Patients were classified according to the number and location of the fractures. Pearson's correlation coefficient was used to assess the relationships between the type of fractures and sagittal alignment. RESULTS: A total of 673 chronic fractures were detected in 249 patients with a mean number of vertebral fractures per patient of 2.7 ± 1.9. Patients were divided into 9 subgroups according to the location and the number of fractures. Surprisingly, any of the aggregated parameters used to assess sagittal alignment exceeded the threshold defined for malalignment. In the second part of the analysis, 41 patients with sagittal malalignment were identified. In this subpopulation, an overrepresentation of patients with lumbar fractures (34% vs. 11%) and an under-representation of thoracic fractures (9% vs. 34%) were reported. We also observed that patients with 3 or more lumbar or thoracolumbar fractures had an increased risk of sagittal malalignment. CONCLUSIONS: Lumbar fractures and/or multiple fractures at the lumbar or thoracolumbar regions are risk factors for sagittal malalignment in patients older than 70 years old. Although patients show a remarkable capacity to compensate, fractures at the lumbar and thoracolumbar regions need closer monitoring.